Powerful partnership: crosstalk between pannexin 1 and the cytoskeleton
Andrew Kenneth Jameson Boyce, Leigh Elizabeth Wicki-Stordeur and Leigh Anne Swayne
Journal Name:
Frontiers in Physiology
ISSN:
1664-042X
Article type:
Mini Review Article
Received on:
01 Nov 2013
Accepted on:
13 Jan 2014
Provisional PDF published on:
13 Jan 2014
Frontiers website link:
www.frontiersin.org
Citation:
Boyce AK, Wicki-stordeur LE and Swayne L(2014) Powerful
partnership: crosstalk between pannexin 1 and the cytoskeleton.
Front. Physio. 5:27. doi:10.3389/fphys.2014.00027
Article URL:
http://www.frontiersin.org/Journal/Abstract.aspx?s=664&
name=membrane%20physiology%20and%20membrane%20biophysics&
ART_DOI=10.3389/fphys.2014.00027
(If clicking on the link doesn't work, try copying and pasting it into your browser.)
Copyright statement:
© 2014 Boyce, Wicki-stordeur and Swayne. This is an open-access
article distributed under the terms of the Creative Commons
Attribution License (CC BY). The use, distribution or reproduction
in other forums is permitted, provided the original author(s) or
licensor are credited and that the original publication in this
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use, distribution or reproduction is permitted which does not
comply with these terms.
This Provisional PDF corresponds to the article as it appeared upon acceptance, after rigorous
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Mini-review
Powerful partnership: crosstalk between pannexin 1 and the
cytoskeleton
Andrew K.J. Boyce1§, Leigh E. Wicki-Stordeur1§, Leigh Anne Swayne1,2,3,4*
1
Division of Medical Sciences, Island Medical Program, University of Victoria, Victoria,
British Columbia, Canada
2
Department of Biology, University of Victoria, Victoria, British Columbia, Canada
3
Department of Biochemistry and Microbiology, University of Victoria, Victoria, British
Columbia, Canada
4
Department of Cellular and Physiological Sciences, University of British Columbia,
Vancouver, British Columbia, Canada
§
these authors contributed equally
* Correspondence should be directed to:
Dr. Leigh Anne Swayne
University of Victoria
3800 Finnerty Road, Victoria, BC CANADA V8P 5C2
[email protected]
Word count: 1,927
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Abstract
The roles of pannexin 1 (Panx1) large-pore ion and metabolite channels are becoming
recognized in many physiological and pathophysiological scenarios. Recent evidence has
tightly linked Panx1 trafficking and function to the cytoskeleton, a multi-component
network that provides critical structural support, transportation, and scaffolding functions
in all cell types. Here we review early work demonstrating the mechanosensitive
activation of Panx1 channels, and expand on more recent evidence directly linking Panx1
to the cytoskeleton. Further, we examine the reciprocal regulation between Panx1 and the
cytoskeleton, and discuss the involvement of Panx1 in cytoskeletal-regulated cell
behaviors. Finally, we identify important gaps in the current knowledge surrounding this
emerging Panx1-cytoskeleton relationship.
Keywords
Pannexin, Panx1, cytoskeleton, actin, mechanosensitive channels, mechanotransduction
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i. Introduction
Mechanical forces shape virtually all biological processes in myriad ways (for a recent
review see Lim et al., 2010). The cytoskeleton is a complex interconnected protein
meshwork that plays a critical role in cellular biomechanics. Its many components and
accessory/regulatory proteins provide structural stability and shape, conduits for the
transport of vesicles and macromolecules, and scaffolding for receptors and ion channels.
It also communicates with multiple signaling pathways within and outside of cells to
modulate these activities in response to the ever-changing demands of cells and their
environments (Jaqaman and Grinstein, 2012). Mechanosensitive channels provide an
important means of crosstalk between chemical and mechanical signaling systems. These
are channels that pass molecules and/or ions in response to stretch, and are often
intimately associated with the cytoskeleton (reviewed in Hamill, 2006).
The pannexins (Panxs) were initially discovered as homologs to the innexin invertebrate
gap junction protein family (Panchin et al., 2000). The initial electrophysiological
characterization of Panx1 channels provided evidence of a large conductance activated by
membrane depolarization (Bruzzone et al., 2003). Soon after this ground-breaking
finding, Bao and colleagues (Bao et al., 2004) made a further striking discovery. They
uncovered an activation mechanism relating the activation of Panx1 to mechanical
deformation; and they provided the first demonstration that Panx1 can form single
membrane mechanosensitive channels. They also provided the first evidence for the role
of Panx1 in adenosine triphosphate (ATP) release, which is perhaps one of the most well
known features of these large pore channels.
These expression system findings have since been expanded to erythrocytes (Locovei et
al., 2006), lung epithelium (Seminario-Vidal et al., 2011;Richter et al., 2014), and more
recently, neurons (Xia et al., 2012). Further, Panx1 has been shown to physically interact
with the actin cytoskeleton (Bhalla-Gehi et al., 2010;Wicki-Stordeur and Swayne, 2013)
and the expression of Panx1 exhibits a significant level of control over multiple
cytoskeletal elements (Penuela et al., 2012). Here we discuss these findings and identify
key knowledge gaps that will be important to further unravel the potentially powerful
relationship between Panx1 and the cytoskeleton.
ii. Activation of Panx1 by Mechanical Stress
The first demonstration of stretch-mediated Panx1 opening resulted from work in an
ectopic expression system by Bao and colleagues in 2004 (Bao et al., 2004). The authors
investigated whether Panx1 exhibits the properties of a mechanical conduit for ATP by
expressing human Panx1 in Xenopus oocytes. In cell-free and cell-attached membrane
patches, they observed a large conductance attributed to Panx1 expression that exhibited
depolarization-dependent activation associated with ATP release. To test for
mechanosensitive properties, they used single channel patch clamp coupled with a
negative pressure stimulus (via suction applied to the patch pipette). This mechanical
stimulation superseded voltage dependent activation, as it occurred over a wide range of
membrane potentials.
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A network of actin, known as the cellular ‘cortex,’ forms a tight association with the
plasma membrane acting as molecular scaffold for ion channels and receptors (recently
reviewed in Salbreux et al., 2012). While it is sometimes assumed that the cytoskeleton is
not present in excised membrane patches in electrophysiological experiments, it is in fact
normally present unless specific measures are taken to disrupt the tight
cytoskeleton/membrane association (recently reviewed in Hamill, 2006). For example,
amongst several groups investigating this intriguing question, by elegantly combining
scanning force microscopy with patch-clamping techniques Sakmann’s lab (Horber et al.,
1995) confirmed the continued presence of the cytoskeleton in cell-free membrane
patches. Further, a recent elegant study has demonstrated that the actin cytoskeleton
functions as a ‘molecular device’ in the activation of mechanosensitive channels by both
concentrating and conducting the forces required for channel opening (Hayakawa et al.,
2008). Although this has not yet been directly tested in the context of Panx1 channels, it
is certainly of interest in light of the recent discovery of the Panx1 physical association
with actin (Bhalla-Gehi et al., 2010;Wicki-Stordeur and Swayne, 2013).
Although quite unlike one another in many ways, erythrocytes, lung epithelium and
neurons are all linked by their responsiveness to mechanical deformation through Panx1mediated ATP release. Locovei and colleagues (Locovei et al., 2006) observed that
Panx1 is present in human erythrocytes, and mediates ATP release and ion flux in
response to depolarization and mechanical stretch elicited by pressure in the patch
pipette. Another group (Seminario-Vidal et al., 2011), later revealed the role of Panx1 as
the ATP conduit responsive to bronchial and tracheal epithelial cell swelling (via
hypotonic challenge). Interestingly, their data pointed to a mechanism by which RhoA, a
regulator of the actin cytoskeleton in the formation of stress fibers, transduces cell
swelling to Panx1 opening. Recently, Richter and colleagues confirmed the role of Panx1
in ATP release from lung epithelial cells in response to stretch. In this case ATP release
via Panx1 was elicited by changes in hydrostatic pressure (Richter et al., 2014). An
intriguing downstream effect of the hydrostatic pressure-induced ATP release from cells
was a concomitant activation of KATP channels. It will be interesting to see whether this
functional relationship is relevant to other cell types in which Panx1 and KATP channels
are co-expressed. More recently, another group (Xia et al., 2012) confirmed the
involvement of Panx1 in mechanical deformation-mediated ATP release of retinal
ganglion neurons using both a hypotonic solution paradigm and a special cell-stretching
chamber.
While mechanical stretch-mediated ATP release can be a physiological phenomenon for
erythrocytes and airway epithelia, it is normally associated with pathophysiology in the
context of nervous system. Here, mechanical stretch via impact-mediated axonal
deformation or secondary to swelling is associated with neuronal injury (recently
reviewed in Laplaca and Prado, 2010). We recently showed, however, that nervous
system resident neural stem and progenitor cells, migrating neuroblasts and newborn
neurons also express Panx1 (Wicki-Stordeur et al., 2012;Wicki-Stordeur and Swayne,
2013). These cells are normally subject to intense and differing mechanical forces from
the time they are born through their journey along the rostral migratory stream under
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physiologically normal conditions. These forces are elicited through the influence of
multiple types of extracellular matrix proteins and various geometrical constraints
(reviewed in Barros et al., 2011 and Moore and Sheetz, 2011).
iii. Panx1 directly interacts with the actin cytoskeleton
Bhalla-Gehi and colleagues first demonstrated that ectopically expressed Panx1 interacts
with actin (through the C-terminus of Panx1), and that actin microfilaments are critical
for Panx1 trafficking to and stability at the plasma membrane (Bhalla-Gehi et al., 2010).
Cytochalasin B treatment, an actin filament-destabilizing compound, significantly
disrupted the plasma membrane distribution and mobility of Panx1-EGFP in the breast
cancer-derived, BICR-M1Rk cell line. In contrast, Panx1-EGFP was insensitive to
nocodazole-mediated disruption of microtubules.
Actin and its modulator, actin-related protein 3 (Arp3), were two of several cytoskeletal
proteins we recently identified as Panx1-interacting proteins by immunoprecipitation
coupled to liquid chromatography and tandem mass spectrometry (LC-MS/MS). We
additionally co-precipitated endogenous Panx1, actin and Arp3, further supporting the
idea that these physical interactions occur naturally and are relevant to Panx1 function
and signaling. Arp3 closely resembles actin monomers in structure and is part of the
seven subunit Arp2/3 actin-modifying complex (reviewed in Firat-Karalar and Welch,
2011). In fact, Arp2/3 functions as a nucleation site for new microfilaments, which
effectively generates a Y-branched network that allows for actin-mediated mechanical
force generation (Mogilner, 2006).
iv. Panx1 is implicated in cell behaviors reliant on actin remodeling
Using pharmacological tools (probenecid), siRNA-mediated Panx1 knockdown and
plasmid-mediated Panx1 overexpression, we further determined that Panx1 has a major
influence on neurite outgrowth and cell migration in Neuro-2a cells and ventricular zone
neural stem and progenitor cells (Wicki-Stordeur and Swayne, 2013). We found that
Panx1 is positively associated with cell migration, whereas it negatively regulates neurite
outgrowth. Neurite extension and cell migration are two cellular behaviors that are
heavily reliant on complex coordination of both actin and mictotubular cytoskeletal
dynamics (recently reviewed in Schaefer et al., 2008; Kaverina and Straube, 2011;
Salbreux et al., 2012).
An earlier study on C6 glioma cells engineered to express Panx1, demonstrated that
ectopic Panx1 overtakes control of the actomyosin system to accelerate the compaction of
multicellular C6 glioma aggregates. Furthermore, the authors observed an enhancement
of ATP release attributable to Panx1 overexpression, as well as P2X7 receptor modulator
sensitivity to the Panx1-mediated changes in cell compaction implicated in the
remodeling. In addition to these predictable observations, the presence of Panx1 also had
a significant impact on the distribution of the actin cortical network.
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Work by several groups had earlier established a connection between P2X receptors and
the actin cytoskeleton (Kim et al., 2001;Pubill et al., 2001;Pfeiffer et al., 2004).
Essentially, P2X7 receptors were shown to interact with actin (Kim et al., 2001), while
other groups demonstrated that ATP activation of P2X receptors promotes actin network
restructuring through an actin-modifying complex to alter cellular morphology (Pubill et
al., 2001;Pfeiffer et al., 2004). In our proteomic analysis of Panx1 interacting partners
(Wicki-Stordeur and Swayne, 2013) we identified actin, Arp3 and other cytoskeletal
regulators, and additional proteins, but we did not detect P2X7 receptors. It is not known
whether P2X7 receptors are bystanders, or are requisite for the crosstalk between Panx1
and the actin cytoskeleton. Further, whether their involvement is cell-type specific or
state-specific (physiological versus pathophysiological; see Morelli et al., 2003 and
Homma et al., 2008) remains to be determined.
v. Other effects of Panx1 expression on the cytoskeleton
Not only is it likely that Panx1 functionally interacts with the cytoskeleton, but it can also
alter the cytoskeletal proteome, as recently shown by Penuela and colleagues (Penuela et
al., 2012). This group investigated the role of Panx1 in melanoma tumorigenesis and
metastasis, and found that increased Panx1 expression correlated with tumour
‘aggressiveness.’ An shRNA-mediated reduction in Panx1 expression was able to revert
the tumor cells to a more melanocytic phenotype (reduced cell migration, increased
melanin production and process formation). Using a 2D gel/mass spectrometry approach,
the authors identified two important cell structure proteins that were down regulated by
the reduction in Panx1, vimentin, an intermediate filament protein, and beta-catenin, an
important regulator of cell adhesion. Earlier, Lai and colleagues demonstrated that
ectopic expression of Panx1 in C6 glioma cells resulted in a dramatically altered cell
morphology (Lai et al., 2007). Panx1 expression led to a flattened morphology quite
distinct from the spindle-shaped morphology normally exhibited by these cells. The
precise cytoskeletal alterations resulting in this striking change in cell shape were not
identified.
These studies along with our recent discovery that modulating Panx1 expression and
function has a dramatic impact on neurite outgrowth in Neuro-2a cells and ventricular
zone neural stem and progenitor cells (Wicki-Stordeur and Swayne, 2013) suggest that
Panx1 is an important cytoskeletal regulator.
vi. Concluding remarks
It is becomingly increasingly clear that the functional role of Panx1 in cells is closely tied
to the cytoskeleton. Panx1 is sensitive to stretch, is involved in cytoskeletal-associated
cell behaviors and physically interacts with actin. Further, Panx1 exerts influence on the
expression of cytoskeletal proteins and when ectopically expressed, can infiltrate and
overtake control of the actin cytoskeleton, even though it is not normally present. This
suggests that Panx1 is likely a powerful regulator of the cytoskeleton in cells in which it
is endogenously expressed.
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We are now working on unraveling the mechanistic details underlying the crosstalk
between Panx1, actin, the Arp2/3 complex and the other cytoskeletal elements, including
elements associated with microtubular dynamics uncovered by our unbiased proteomic
analysis of Panx1 interactors in cells that endogenously express Panx1. By studying these
interactions, we hope to gain detailed information on the molecular players that are key to
Panx1/cytoskeletal crosstalk. This work will bridge significant knowledge gaps in our
understanding of the physiological and pathophysiological roles of Panx1.
Conflict of Interest Statement
We have no competing interests to declare.
Contributions
LAS conceived of the topic, while LAS, AKJB, and LEWS co-wrote the body of the
manuscript. AKJB and LEWS together wrote the abstract. LAS, AKJB and LEWS
revised the manuscript. All authors approve of the manuscript and its contents.
Acknowledgments
Research in the Swayne lab is supported by an NSERC Discovery grant, a Heart and
Stroke Foundation Partnership for Stroke Recovery grant and a University of Victoria
Division of Medical Sciences startup grant. AKJB is supported by an NSERC Canadian
Graduate Scholarship – Masters and a University of Victoria Graduate Award. LEWS is
supported by a Vanier Canada Graduate Scholarship (NSERC), a Howard E. Petch
research scholarship, and an Edythe Hembroff-Schleicher graduate scholarship. We thank
the Victoria Foundation Willard and Elva Dawson Fund for previous stipend support for
AKJB and LEWS. We are grateful to the Canadian Foundation for Innovation and the
British Columbia Knowledge Development Fund for granting funds for our confocal
microscope.
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